The astonishing complexity of the immune system is its greatest strength. The 1012-1014 possible antibody specificities, the delicate interplay between the various regulatory and effector cells, the restriction of T cell responses according to MHC antigens; all these contribute to the ability of the host to effectively react against infectious agents and other antigens perceived as foreign. But this diversity has its drawbacks. Mistakes happen: the target of a response may turn out to be a normal self protein; inflammatory responses are misregulated; and normal responses are undesirably directed against grafts and transplanted cells. Under these-circumstances, the complexity of the system makes diagnosis and therapy extremely difficult.
The profile of cytokines produced by CD4+ T cells during an immune response determines the nature of effector functions which develop and regulates the outcome of an immune response. Production of IL-2 and IFN-γ during Th1-dominated responses is associated with vigorous cell-mediated immunity, the induction of IgG2a and inhibition of IgE synthesis, and with resistance to intracellular pathogens. In contrast, the production of IL-4, IL-5 and IL-10 during Th2-dominated responses is associated with humoral immunity and protection from autoimmune pathology. Overproduction of Th2-cytokines by allergen-specific CD4+ T cells can result in the development of allergic disease and asthma, while Th1 cells have been associated with a variety of pro-inflammatory diseases.
One approach to immune associated diseases is immunotherapy. Immunotherapy has proven to be effective when used properly, and it is hoped that advances in immunologic intervention will further improve the efficacy. Alternative approaches have attempted to use cytokines to shift the immune response. IL-12, a heterodimeric cytokine produced by macrophages and dendritic cells, is potent in driving the development of Th1 cytokine synthesis in naive and memory CD4+ T cells. Other cytokines, such as IL-13 and IL-4, have been associated with the differentiation of T cells to a Th2 type.
Atopy, which includes asthma, allergic rhinitis, and atopic dermatitis, is a complex trait that arises as a result of environmentally induced immune responses in genetically susceptible individuals. The prevalence of all atopic diseases has dramatically increased in industrialized countries over the past two decades. Asthma is the most common chronic disease of childhood and affects more than 15 million individuals in the United States, leading to direct treatment costs exceeding $11 billion per annum. Epidemiological studies have suggested that the increase in asthma prevalence results from changes in hygiene and from reduced frequency of infections (e.g., tuberculosis or hepatitis A) within industrialized society. However, the specific molecular pathways that result in the increased asthma prevalence, and the genetic polymorphisms that confer asthma susceptibility are poorly understood.
Expression of asthma is influenced by multiple environmental and genetic factors that interact with each other in non-additive ways, complicating the identification of asthma susceptibility genes. Asthma susceptibility has been linked to several chromosomal regions, but with resolution no better than 5-10 cM, in which there are usually hundreds of candidate genes. Moreover, because the effects of genetic variation in any single gene are likely to have only modest effects in the overall pathogenesis of asthma, and because gene-gene and gene-environment interactions confound the analysis, the location of putative susceptibility genes to regions amenable to positional cloning has proven difficult to refine. Nevertheless, asthma susceptibility has been linked to chromosomes 5, 6, 11, 14, and 12. Of these, chromosome 5q23-35 has received the greatest attention because it contains a large number of candidate genes(11, 12, 13, 14, 15, 16, 17, 18), including IL-9, IL-12p40, the β-adrenergic receptor, and the IL-4 cytokine cluster, which contains the genes for IL-4, IL-5, and IL-13. However, the large size of the linked region of 5q complicates its analysis, and a gene for asthma from this site has not yet been conclusively identified.
Related Publications
The genetic sequence of the human hepatitis virus A cellular receptor may be found in Genbank, accession number XM—011327. A related sequence is provided in Genbank, accession number BAB55044. Monney et al. (2002) Nature 415:436 describe cell surface molecules expressed on Th1 cells. U.S. Pat. Nos. 5,721,351, 6,204,371, 6,288,218 relate to sequences corresponding to a mouse TIM-3 allele.